Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen-activated protein kinases (MAPK) has been discovered. Members of this family are Ser/Thr kinases that activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (1996)]. MAPKs are themselves activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents.
One particularly interesting MAPK is p38. p38, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, was isolated from murine pre-B cells that were transfected with the lipopolysaccharide (LPS) receptor, CD14, and induced with LPS. p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mice. Activation of p38 has been observed in cells stimulated by stress, such as treatment of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF.
Inhibition of p38 kinase leads to a blockade on the production of both IL-1 and TNF. IL-1 and TNF stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 and have been implicated in acute and chronic inflammatory diseases and in post-menopausal osteoporosis [R. B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)].
Based upon this finding, it is believed that p38, along with other MAPKs, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune disease, cell death, allergies, osteoporosis and neurodegenerative diseases. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. Other disease associated with IL-1, IL-6, IL-8 or TNF overproduction are set forth in WO 96/21654.
Many molecules possessing medicinally important properties against various targets, including MAPKs, comprise diaryl amines. One example of this is a class of molecules identified as potent p38 MAP kinase inhibitors (see, e.g., WO 99/58502 and WO 00/17175). However, although they are effective as drugs, there are few ways to make aryl amine-containing molecules without a significant amount of by-product. Palladium-catalyzed couplings of an aryl amine and aryl halide have been the traditional strategy to produce a molecule comprising a diaryl amine. However, problems with over-addition of the aryl halide partner to the amine have traditionally resulted in low yields and purities when a primary aryl amine is employed. For this reason, primary amines are not commonly employed substrates for this transformation, which has limited the scope of the palladium-catalyzed coupling reaction.
Accordingly, the need exists for a process for the facile synthesis of diaryl amines and analogues thereof that avoids the problem of over-arylation, to obtain diaryl amines in high yield and purity. There also exists a need for intermediates produced by such a process.